Pharmaceutical compositions containing quaternary ammonium compounds and a steroid



This invention relates to the adsorption of quaternary ammonium saltsand is more particularly concerned with a composition whereby the oraladministration of quaternary ammonium salts results in greatly increasedphysiological effects.

Many quaternary ammonium organic compounds have been shown to haveuseful pharmaceutical properties. However, these materials are usuallyadministered direct 1y into the blood stream, because their relativelypoor and erratic absorption from the gastro intestinal tract results invarying characteristics for the same drug when administered orally.Additionally, the effect usually expected from the quaternary ammoniumcompound is considerably less, due to the poor absorption. Of course,;such limitations on the use of these pharmaceutical quaternary ammoniumcompounds has constituted a limitling factor in their wide overallacceptance. Generally speaking, the use of quaternary ammonium compoundsfor the purpose of lowering blood pressure (hypotensive agents) hasgained significant recognition in recent years. Necessarily, much of theadministration of these hypotensive agents should be accomplishedorally, to eliminate the necessity for the careful control andprofessional assistance required where such materials are administereddirectly into the blood stream. In the field of antispasmodics, thereare quaternaries which show a higher degree of activity than thecorresponding tertiary amine, upon comparison by certain quantitativetest methods. In practice however, the quaternary antispasmodics arerelatively poorly absorbed when administered orally and have notgenerally been found suitable for practical application. In generalthen, it may be said that many quaternary compounds with usefulactivities when administered by parenteral routes are limited in theirapplication, be-

cause the generally more convenient oral route is unavailable due to therelatively poor degree of absorption of these materials and the erraticeffects that result.

It is, therefore, a principal object of the present invention to providea composition which allows markedly improved absorption of quaternaryammonium compounds upon oral administration. Still another object of thepresent invention is the provision of such a composition which allowscertain quaternary ammonium compounds to be administered orally withgenerally uniform results. Another object of the present invention is toprovide a composition of matter containing a therapeutically activequaternary ammonium compound in admixture with a steroid acid. Anotherobject of the present invention is to provide such a composition whichcontains between and 400 milligrams per dose of such steroid acid, inintimate mixture with a therapeutic quantity of a quaternary ammoniumcompound. Other objects will become apparent hereinafter.

The present invention contemplates a mixture of therapeutically activequaternary ammonium compounds in intimate mixture with steroid acids,such as bile acids or a mixture of the bile acids or their salts, all ofwhich contain a cyclopentanopolyhydrophenanthrene nucleus with a moietycontaining a carboxy group attached to the 17-position. Representativesteroid acids, of which the so-called bile acids are examples, includedwithin the tes Patent scope of the present invention include, forexample, cholic acid, dehydrocholic acid, lithocholic acid,dihydroxycholanic acid, isodesoxycholic acid, norcholanic acid,diketocholanic acid, cholanic acid, allocholanic acid, choleic acid,dihydroxycholenic acids, desoxybilianic acid, glycocholic acid,ketocholanic acid and other bile acids, etc., mixtures of these andother steroid acids containing a cyclopentanopolyhydrophenanthrenenucleus and the carboxy group somewhere attached to or through the17-position, as well as readily hydrolizable salts of these acids.Representative salts which are suitable include, for example, sodium,potassium, calcium, magnesium, lithium, etc. that is, salts which arewater-soluble, and readily hydrolizable by the digestive tract.

Quaternary ammonium salts which are suitable include monoquaternary anddi-quaternary organic compounds having pharmacologic activity asantispasmodic agents, cardiovascular agents, hypotensive agents,curarimimetic agents, and in general those materials which arequaternary organic compounds, suitable for oral administration. Thegermicidal surface-active type of quaternary compounds are not includedwithin the scope of the present invention, since they are normallyadministered topically. Included wtihin the scope of the mono-quaternaryand di-qu aternary 'organic compounds particularly suitable for thecombination are, for example, tetraethylamrnonium, hexamethonium,pentamethonium, pentapyrrolidinium salts, homatropine methylbromide,hexamethylene bis [2 (1 methyl 9 pyrid 3,4b indolium) ldibromide,hexamethylene bis [2 (1,2 dimethyl 1,2,3,4- tetrahydro 9 pyrid 3,4bindolium)]dibromide, tetramethylene bis [2 (1 methyl 9 pyrid3,4bindolium)]dibromide, pentamethylene bis [2 (1- methyl 9 pyrid 3,4bindolium)]dibromide, pentamethylene bis [2 (1,9 dimethyl 9 pyrid3,4bind'olium) Jdiiodide, pentamethylene bis [2 (1 propyl- 9 pyrid 3,4bindolium)]dibromide, hexamethylene bis [2 (1,9 dimethyl 9 pyrid 3,4bindolium)] dibromide, 1 (1 methyl 9 pyrid 3,4b indolium) 3(diethylmethylammonium)propane dibromide, 1 (1- methyl 9 pyrid 3,4bindolium) 6 (trimethylammonium)hexane dibromide, 1 isoquinolinium 6(trimethylammonium)hexane dibromide, 1 (1,9 dimethyl- 9 pyrid 3,4bindolium) 3 (trimethylammonium) propane dibromide, l (1 methyl 9 pyrid3,4bindolium) 3 (trimethylammonium) propane dibromide, 1 isoquinolinium3 trimethylammonium propane dibromide, 1 (1 methyl 9 pyrid 3,4bindolium) 3- (N methylpyrrolidinium) propane dibromide, l (1- methyl 9pyrid 3,4b indolium) 5 (trimethylammonium)pentane dibromide, 1 (1 methyl9 pyrid- 3,4b indolium) 3 (N methylpi-peridinium)propane dibromide, 1 (9pyrid 3,4b indolium) 3 (trimethylammonium)propane dibromide, latropinium 3- (trimethylammonium)propane dibromide, l (isoquinolinium) 3(N methylpyrrolidinium)propane dibromide, l tropinium 3(trimethylammonium)propane dibromide, 1 (2 methyl 1,2,3,4tetrahydroisoquinolinium) 3 (trimethylammonium)propane dibromide, 1 (4bromoisoquinolinium) 3 trimethylammonium propane dibromide, l [4-'(phenylthioethyl) pyridinium] 3 (trimethylammonium)propane dibromide,1- (1,2 dimethyl l,2,3,4 tetrahydro 9 pyrid 3,4bindolium) 3(trimethylammonium)propane dibromide, 1 (l methylisoquinolinium) 3trimethylammonium propane dibromide, 1 (1,9 dimethyl 9 pyrid3,4bindolium) 3 (N methylpyrrolidinium)propane dibromide, 1 [4 (3indoleethenyl) pyridinium] 3- (trimethylammonium) propane dibromide, 1(2- ethyl 1,2,3,4 tetrahydroisoquinolinium) 3(trimethylammonium)-propane dichloride, 1 (2 methyl 1,2,3, 4tetrahydroisoquinolinium) 3 (N methylpyrrolidinium) propane dibromide, 1[4 (naphthylethenyl)- pyridinium-l 3 (trimethylammonium) -propanedibromide, 1 (4 benzylpyridinium) 3 (trimethylammonium)-propanedibromide, 1 [4 (3 i ndolethyl) pyr d iu r m hy m n m) r pane dibronude,1 [4 (phthalamidoethyl) pyridinium] 3 (trimethylammonium) propanedibromide, 1 (tropinonium) 3 trimethylam'monium-propane dibromide, 1-(isoquinolinium') 4: (N methylpyrrolidinium) -butane dibromide, 1- (4stilbazolium) 3 (trimethylammonium) propane dibromide, 1 (N methyl 4benzylpiperidinium) 3 trimethyl-ammonium-propane dibromide, 1 (1,2dimethyl 1,2,3,4 tetrahydroisoquinolinium) 3 trimethylammonium propanedibromide, 1- tropanium 3 trimethylammonium propane dibromide, 1 (4indeneethylpyridinium) 3 (trimethylammonium) propanedibromide, 1 [4' (3benzoxypropyl) pyridinium] 3- ('trimethylammonium) propane dibromide, 1t-ropinium 3 (N --methylpiperidinium) propane dibromide, l' (tropinium)3 (N- methylpyrrolidinium) propane dibromide, 1- [2 (3-indoleethyl)pyridinium-] 3 trimethylammonium propane dibromide, 1 (2ethyltetrahydroisoquinolinium)- 4 (trimethylammonium) butane dibromide,1 (2- methyltetrahydroisoquinolinium) 2 (trimethylamm'onium) ethanediodide, 1 (1 methyl 4 benzylpiperidinium) 2 (trimethylammonium) ethanediiodide, l- [4 1 methyl 3 indoleethyl-)pyridinium] 3 trimethylammoniumpropane dibromide, 1' (2 ethylisoindolinium) 3 (trimethyl'ammonium)propane dibromide, 1 [2 (1 naphthylethyl)pyridinium] 3 trimethylammoniumpropane dibromide, 1 [2 1 indeneethyl) pyridinium] 3 trimethylammoniumpropane dibromide, 2 diphenylmethylisoquinolinium bromide, 9 fiuorenylisoquinolinium bromide, 2 diphenylmethyl; 1 methyl 9 pyrid 3,4bindoliumbromide, etc.

The combination is usually administered as a capsule, tablet orsolution. Because of the bitter taste which is normally associated withthe steroid acids, administration by solution is not as desirable as itis by tablet or capsule. The amount of steroid acid which will be usedper dose, that is, per tablet, per capsule, or per volume ofliquid-dose, is most suitably between the range. of 25 milligrams to 400milligramsdepending tosome extent on the weight dosage of thetherapeutic agent. Normally between 100 to 300 milligrams per capsule ordose is the more preferred. In; the case ofI-(Z-ethyl-l,2,3,4-tetrahydroisoquinolinium)3-(trimethylammonium)propaue disalt, 200 milligrams of the quaternaryammonium bromide or chloride and'ZQO milligrams of cholic acidconstitutes a desirable ratio. Hexamethonium chloride may be used intablets ranging from 100 to 300 milligrams of quaternary incombinationwith quantities ranging from 100 to 300-grams 'of' one of thesteroid acids. Of. course the [particular anion associated with thetherapeutic quaternary ammonium compound should be stable and non-toxic,but is otherwise not critical. Pentapyrrolidiniummay beused in 50 to 100milligram tablets combined with 50 to 200 milligrams of the steroidacid. In the case of 1-[4-( l-methyl-3-indoleethyl)pyridinium]-3-trimethylammonium-propane dibromide, between 25 and 75 milligrams of thequaternary and 50 to 200 milligrams of asteroid acid per dose isadesirable ratio.

Preparation of the composition of the present invention is readilyaccomplished by intimately mixing the steroid acid and the quaternary.Conventional equipmentv may be employed. Where tableting is to be theend result, the use of excipients, fillers, coloring matter, etc., iscontemplated. With capsules, the addition of the mixture directly to thecapsule is usually satisfactory. Where solutions are used, the mixtureis dissolved. in a suitable sol-. vent, which may contain other solutessuclras buffers, and the concentration regulated. Both pharmacologicaland-clinical studieshavelindicated that the absorption of 4 thequaternary ammonium compound compounded as discussed above andadministered orally'is enhanced greatly: For example, in animals, uponthe oral administration of hexamethonium, in an amount of 5 milligramsper kilogram of body weight, with 10 milligrams per kilogram of steroidacid, a blood pressure fall of 50 percent with 4.5 hours required'toreturn to pre-fall level was noted. This is in direct contrast to theoral administration of 5 milligrams per kilogram of hexamethoniumwithout the steroid acid: which resulted in: a 45 percent blood pressurefall with only 1.0 hour required to return to pre-fall level.

Various modifications'may be made in the composition of the presentinvention wtihout departing from the spirit or scope thereof and I'-limit myself only as defined in the appended claims.

I claim: L

1. A composition of matter having enhanced pharmacologic action uponoral administration comprising: a physiologically-active,non-surface-active, quaternary arn-' monium compound per sepharmacologically effective upon oral administration in intimate mixturewith a compound selected from the group consisting ofcyclopentanopolyhydrophenanthrenes having a moiety. attached at the17-position, said moiety comprising a carboxyl group, and hydrolyzablesalts, of said cyclopentanopolyhydrophenanthrenes. 2. A composition ofmatter having enhanced pharmacologic action upon oral administrationcomprising: a

' physiologically-active, non-surface-active, quaternary ammonium,compound per se pharmacologically efiective upon oral administration inintimate mixture with between 25 and 400 milligrams per dose of acyclopentanopolyhydrophenanthrene having a moiety attached at the 17-position, said moiety comprising a carboxyl group.

3. A composition of matter having enhanced. pharmacologicv action uponoral administration comprising: a physiologically-active,non=surface-active, bis-quaternary ammonium salt per sepharmacologically effective upon oral administration in intimate mixturewith between and 300 milligrams per dose of acyclopentanopolyhydrophenanthrene having a moiety attached at the17-position, said moiety comprising a carboxyl group.

4. A, composition of matter having enhanced pharmacologic, action uponoral administration comprising: between about 25 and about300'milligrams per dose of a physiologically-active, non-surface-active,bis-quaternary ammonium salt per sepharmacologically eifective upon oraladministration. in intimate mixture with between about. 100 and about300 milligrams per dose of a bile acid.

5. A composition of matter having enhanced therapeutic; action upon oraladministration comprising: hexamethonium in intimate mixture with bileacid.

6. A composition of matter having enhanced thera-. peutiepropertieswhich comprises: 1-(2-ethyll,2,3,4-tetrahydroisoquinolinium) 3(trimethylammonium)-propane dibromide in intimate mixture with cholicacid.

7. A process comprising orally administering to an animal a compositionof matter comprising: a physiologically-active, non-surface-active,quaternary ammonium compound per se pharmacologically effective uponoral administration in intimate mixture with a compound selected fromthe group consisting of cyclopentanopolyhydrophenanthrenes having amoiety attached at the 17- position,-said,moiety comprising a carboxylgroup, and hydrolyzable' salts of saidcyclopentanopolyhydrophenanthrenes.

24th ed., 1947, p. 807, Lippincott

1. A COMPOSITION OF MATTER HAVING ENHANCED PHARMACOLOGIC ACTION UPONORAL ADMINISTRATION COMPRISING: A PHYSIOLOGICALLY-ACTIVE,NON-SURFACE-ACTIVE, QUATERNARY AMMONIUM COMPOUND PER SEPHARMACOLOGICALLY EFFECTIVE UPOM ORAL ADMINISTRATION IN INITMATE MIXTUREWITH A COMPOUND SELECTED FROM THE GROUP CONSISTING OFCYCLOPENTANOPOLYHDROPHENANTHRENES HAVING A MOIETY ATTACHED AT THE17-POSITION, SAID MOIETY COMPRISING A CARBOXYL GROUP, AND HYDROLYZABLESALTS OF SAID CYCLOPENTANOPOLYHYDROPHENANTHRENES.